Genetic Determinants of Response to P2Y12 Inhibitors and Clinical Implications.

The CYP2C19 enzyme metabolizes clopidogrel, a prodrug, to its active form. Approximately 30% of individuals inherit a loss-of-function (LoF) polymorphism in the CYP2C19 gene, leading to reduced formation of the active clopidogrel metabolite. Reduced clopidogrel effectiveness has been well documented in patients with an LoF allele following an acute coronary syndrome or percutaneous coronary intervention. Prasugrel or ticagrelor is recommended in those with an LoF allele as neither is affected by CYP2C19 genotype. Although data demonstrate improved outcomes with a CYP2C19-guided approach to P2Y12 inhibitor selection, genotyping has not yet been widely adopted in clinical practice.

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

Comparative Effectiveness and Safety Analysis of Dual Antiplatelet Therapies Within an Integrated Delivery System.

BACKGROUND: Dual antiplatelet therapy is a mainstay of care for percutaneous coronary intervention (PCI) patients; however, uncertainty exists in real-world practice about comparative effectiveness and safety outcomes. OBJECTIVE: To evaluate outcomes of different oral P2Y12 inhibitors in PCI patients. METHODS: We retrospectively studied patients treated between July 1, 2010, and December 31, 2013. Patients received clopidogrel, prasugrel, ticagrelor, or more than 1 antiplatelet (switch) during PCI. Outcomes were evaluated for major adverse cardiovascular events (MACE) and bleeding at 1 year. Propensity score matching with Cox proportional hazards analysis was used to determine predictors of MACE and bleeding. RESULTS: A total of 8127 patients were included: clopidogrel (n = 6872), prasugrel (n = 605), ticagrelor (n = 181), and switch (n = 469). Treatment with prasugrel was associated with the lowest risk of MACE using multivariate regression (odds ratio [OR] = 0.57; 95% CI = 0.36-0.92; P = 0.02). In the propensity score-matched analysis, only the prasugrel group was associated with a lower risk of MACE compared with the clopidogrel group. Clopidogrel was associated with the lowest risk of major bleeding using multivariate regression (OR = 0.64; 95% CI = 0.42-0.98; P = 0.042). Both ticagrelor (hazard ratio [HR] = 2.00; 95% CI = 1.11-3.59) and the switch groups (HR = 1.65; 95% CI = 1.09-2.50) were associated with a greater risk of major bleeding compared with clopidogrel. However, no differences were found in the propensity score-matched analysis. CONCLUSIONS: Dual antiplatelet therapies differed in both MACE and bleeds in a real-world setting of PCI. Prasugrel was associated with fewer MACE, whereas clopidogrel had fewer major bleeding events.

Triple Antithrombotic Therapy With Aspirin, P2Y12 Inhibitor, and Warfarin After Percutaneous Coronary Intervention: An Evaluation of Prasugrel or Ticagrelor Versus Clopidogrel.

BACKGROUND: Triple antithrombotic therapy is used in patients who require systemic anticoagulation and undergo percutaneous coronary intervention (PCI) requiring dual antiplatelet therapy. Bleeding with this combination is significant; however, few studies have described outcomes with the use of newer oral P2Y12 inhibitors in this setting. OBJECTIVES: We aimed to compare outcomes among patients prescribed triple therapy with prasugrel or ticagrelor compared to triple therapy with clopidogrel in patients who underwent PCI and required warfarin. METHODS: We retrospectively evaluated 168 patients who received either prasugrel (n = 32) or ticagrelor (n = 10) and were matched (1:3) to those who received clopidogrel (n = 126) at the time of discharge from the index PCI visit. Matching was performed based on age ±10 years, sex, and indication for PCI. The primary outcome was the incidence of any bleeding during the 12-month follow-up. We also evaluated major adverse cardiovascular and cerebrovascular events (MACCEs). RESULTS: Patient baseline characteristics were similar between groups. There was a significant excess of bleeding in patients who received prasugrel or ticagrelor compared to clopidogrel as part of triple therapy (28.6% vs 12.7%; odds ratio, 3.3; 95% confidence interval, 1.38-8.34). No differences were seen between groups in MACCEs. CONCLUSIONS: The use of prasugrel or ticagrelor as part of triple antithrombotic therapy among patients who underwent PCI and received warfarin was associated with significantly more bleeding compared to patients who received clopidogrel. Therefore, higher potency P2Y12 inhibitors should be used cautiously in these patients.

Pharmacokinetic evaluation of prasugrel for the treatment of myocardial infarction.

INTRODUCTION: Prasugrel is a novel P2Y12 inhibitor approved for treatment of patients with acute coronary syndrome (ACS) who undergo percutaneous coronary intervention (PCI). AREAS COVERED: This article focuses on the pharmacokinetics of prasugrel and recently published pharmacodynamic and clinical studies. The authors searched PubMed and Ovid databases for English language pharmacokinetic, pharmacodynamic and clinical studies which described the use of prasugrel in human subjects and patients, published through October 2013. The keyword 'prasugrel' was used. EXPERT OPINION: Prasugrel exhibits favorable pharmacokinetic and pharmacodynamic properties compared to clopidogrel. These effects have translated to significant clinical benefits, despite the increased bleeding risk, in the context of ACS with primary PCI. Recent clinical trial evidence does not support the use of prasugrel in other ACS settings at this time, including medical management of non-ST segment elevation myocardial infarction and routine pretreatment prior to angiography. Careful patient selection for prasugrel is also imperative, taking into account the need for maintenance dose reductions in certain patient subgroups. Antiplatelet decision making for high-risk patients in the future may be facilitated with the use of both genotypic and phenotypic characteristics, including platelet function, and should be an imperative for future research efforts.

Multidisciplinary team for enhancing care for patients with acute myocardial infarction or heart failure.

PURPOSE: Pharmacists' involvement in a disease management program for the improvement of care of patients with acute myocardial infarction (MI) or heart failure (HF) is described. SUMMARY: Beginning in 2002, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) implemented evidence-based measures in several performance areas, including MI and HF. In 2003, a multidisciplinary team consisting of physicians, clinical pharmacists, nurses, cardiac rehabilitation specialists, nutrition specialists, and case managers was established at Allegheny General Hospital. As of January 2004, hospitals were required to select three core measure sets in order to meet JCAHO accreditation requirements. Pharmacists provided medication evaluation and education for patients in an effort to augment adherence with the JCAHO core measures. These services were facilitated by pharmacists' participation in the development of preprinted orders, clinical pathways, patient-evaluation forms, and written educational materials. Patients targeted for intervention were admitted with a principal diagnosis of MI or HF. JCAHO core measure data for MI and HF were presented from first quarter (Q1) fiscal year (FY) 2005 through Q1 FY 2006. For MI, a consistent improvement in performance to 100% was demonstrated for four of the six criteria. For HF, increases were demonstrated for left ventricular (LV) function assessment, angiotensin-converting-enzyme inhibitor for LV systolic dysfunction, and smoking-cessation counseling. Despite documentation issues regarding discharge instructions, results overall compared favorably with the referenced standard. CONCLUSION: A multidisciplinary team that included pharmacists improved JCAHO core measures for hospitalized patients with MI or HF.

Outcomes and costs of abciximab versus eptifibatide for percutaneous coronary intervention.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) with stent placement are often prescribed glycoprotein IIb/IIIa inhibitors. However, drug selection is often based on clinicians' preference and cost because few studies have directly compared abciximab and eptifibatide. OBJECTIVE: To compare clinical outcomes and total hospital costs of abciximab and eptifibatide in patients undergoing stent placement during PCI in a real-world setting. METHODS: A retrospective cohort analysis was conducted of 960 patients administered abciximab or eptifibatide for intracoronary stent placement between 1999 and 2001 at a tertiary care hospital. The primary outcome was bleeding, defined as major, moderate, or minor according to published criteria. Secondary outcomes included in-hospital death, myocardial infarction, revascularization, and the triple composite endpoint of those outcomes, thrombocytopenia, length-of-stay, and total hospital costs. Pearson's chi(2) analysis, Fisher's exact test, and ANOVA were used for statistical analysis. RESULTS: The frequency of bleeding complications based on severity was similar between abciximab and eptifibatide: major (2.4% vs 2.8%), moderate (12.4% vs 10.5%), and minor (4.0% vs 3.9%), respectively (p = 0.86). Secondary clinical outcomes were also similar between groups (p > 0.05). Total costs for hospitalization were significantly greater for abciximab compared with eptifibatide ($16,383 +/- 6799 vs $14,115 +/- 6285; p < 0.001). Drug acquisition costs were also significantly greater for abciximab compared with eptifibatide ($508 +/- 159 vs $465 +/- 263; p = 0.003). CONCLUSIONS: In patients undergoing stent placement during PCI, abciximab and eptifibatide are comparable in terms of safety and effectiveness despite significant differences in hospitalization and acquisition costs.

Eptifibatide-associated acute, profound thrombocytopenia.

OBJECTIVE: To describe 3 cases of eptifibatide-associated acute, profound thrombocytopenia. CASE SUMMARIES: A 40-year-old black female received eptifibatide 180-microg/kg double bolus followed by a continuous infusion of 2 microg/kg/min for percutaneous coronary intervention (PCI). The platelet count decreased from 308 x 10(3)/mm3 to 2 x10(3)/mm3 4 hours after initiation of eptifibatide. Eptifibatide was discontinued and platelets were transfused. The patient developed a hematoma and petechiae. A 67-year-old white female received the same dosage regimen of eptifibatide for PCI with no serious adverse effects, with the treatment repeated one month later. At that time, she developed chest and back pain, dyspnea, wheezing, and hypotension after the first bolus. Her platelet count decreased from 334 x10(3)/mm3 to 6 x10(3)/mm3 24 hours after initiation. Eptifibatide was discontinued and platelets were transfused. The patient died due to shock. A 72-year-old white male received eptifibatide 180-microg/kg double bolus followed by a continuous infusion of 2 microg/kg/min for acute coronary syndrome. His platelet count decreased from 189 x10(3)/mm3 to 17 x10(3)/mm3, and eptifibatide was discontinued. Eptifibatide was readministered with bivalirudin for PCI once the platelet count increased to 94 x10(3)/mm3. Sixteen hours later, the platelet count decreased to 1 x 10(3)/mm3. Eptifibatide was discontinued and platelets were transfused. The patient developed a hematoma. DISCUSSION: Acute, profound thrombocytopenia is a rare complication of glycoprotein IIb/IIIa inhibitor therapy characterized by a precipitous decline in platelet count to <20 x10(3)/mm3 within 24 hours of therapy. An objective causality assessment revealed that the adverse drug event was probable in 2 cases and possible in the other. CONCLUSIONS: Increasing use of the glycoprotein IIb/IIIa inhibitors and enhanced recognition of the potential for acute, profound thrombocytopenia reinforce the need for more vigilant monitoring and alternative management strategies.